Prazosin, the hydrochloride salt of 2-(4-(2-furoyl)-piperazine-1-yl)-4-amino-6,7-dimethoxy-quinazoline, compound 1 of Table I wherein R is 2-furoyl, is an antihypertensive agent with a chemical structure unrelated to that of any other in use.
Since its introduction, prazosin remains the drug of choice both in human therapy and in laboratory studies of alpha.sub.1 -adrenoreceptors. Many analogs of prazosin have been prepared and patented since that time.
Side effects of a drug are caused by a lack of specificity in drug-receptor interaction. Nearly all drugs interact with several classes of receptors, and thus have multiple effects on physiology, some of which represent undesirable side effects of therapy. Thus, compounds with increased selectivity towards drug receptors are sought that possibly may permit more selective intervention in the organism.
Prazosin has been shown to lower blood pressure in hypertensive patients and in normotensive and hypertensive animals. The mechanism of action of prazosin is presently believed to be based upon a relaxation of peripheral arterioles as a consequence of a functional inhibition of alpha.sub.1 -adrenoceptors. Prazosin exhibits a preferential affinity for postysynaptic alpha.sub.1 -adrenoreceptors, designated as alpha.sub.1.
Considerable progress has recently been achieved in understanding alpha.sub.1 -adrenoreceptor structures. For studies on chemical modification of alpha.sub.1 -adrenoceptors, phenoxybenzamine, N-ethoxycarbonyl-2- ethoxy-1,2-dihydroquinoline (EEDQ), and so-called tetramine disulfides have been used. However, there are a number of disadvantages to the use of these compounds. Phenoxybenzamine is not very specific; in addition to alpha.sub.1 -adrenoceptors, it interacts with alpha.sub.2 -adrenoceptors, histamine receptors, dopamine receptors, and muscarinic receptors. The receptor specificity of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline is also low. In addition this compound must be used at concentrations about 10.sup.4 higher than the more specific chemoreactive labels. The tetramine disulfide, pyrextramine, was used to selectively block peripheral alpha.sub.1 -adrenergic responses. However, more recently, pyrextramine was shown to block peripheral alpha.sub.2 -adrenergic responses as well, which suggests a lack of specificity for alpha.sub.1 -adrenergic responses.
The importance of events mediated by alpha.sub.1 -adrenoceptors is well recognized, including their role as targets for drugs and neurotransmitters initiating the breakdown of phosphoinositides. Much work has been directed at characterizing the alpha.sub.1 -adrenergic binding site. Photoaffinity probes developed and studies by several groups showed specific incorporation of iodinated ligands into a peptide of approximately 80,000 mwt. Other studies have examined the metabolism of alpha.sub.1 -adrenoceptors both in vivo and in cultured cells, using phenoxybenzamine.